A. Field of the Invention
Embodiments of this invention are directed generally to microbiology and medicine. In certain aspects the invention is directed to treatment of Staphylococcus and Streptococcus infection.
B. Description of Related Art
The number of both community acquired and hospital acquired infections have increased over recent years with the increased use of intravascular devices. Hospital acquired (nosocomial) infections are a major cause of morbidity and mortality, particularly in the United States, where it affects more than 2 million patients annually. The most frequent infections are urinary tract infections (33% of the infections), followed by pneumonia (15.5%), surgical site infections (14.8%) and primary bloodstream infections (13%) (Emorl and Gaynes, 1993).
The major nosocomial pathogens include Staphylococcus aureus, coagulase-negative Staphylococci (mostly Staphylococcus epidermidis), enterococcus spp., Escherichia coli, Clostridium difficile and Pseudomonas aeruginosa. Although these pathogens cause approximately the same number of infections, the severity of the disorders they can produce combined with the frequency of antibiotic resistant isolates balance this ranking towards S. aureus and S. epidermidis as being the most significant nosocomial pathogens. Staphylococci can cause a wide variety of diseases in humans and other animals through either toxin production or invasion.
Epithelial barriers are a potent host defense against invasive bacterial infection. Pathogens circumvent this barrier through virulence factors that target specific structural elements of the epithelium, impairing its integrity (Kim et al., 2010). Critical bacterial targets within the epithelium include focal adhesion complexes, apical tight junction proteins, and the cadherin:catenin protein complex that comprises the adherens junction. Staphylococcus aureus is a leading cause of bacteremia, pneumonia, skin and soft tissue infection and lethal toxin-mediated syndromes (Lowy, 1998). This organism exhibits a dual interaction with its human host, existing as a harmless skin commensal and deadly invasive pathogen armed with multiple virulence factors. S. aureus alpha-hemolysin (Hla) is a pore-forming cytotoxin that contributes to the pathogenesis of pneumonia, dermonecrotic skin infection, and corneal infection (O'Callaghan et al., 1997; Kennedy et al., 2010; Bubeck Wardenburg et al., 2007a, 2007b). Further, Hla potentiates the penetration of S. aureus toxic shock syndrome toxin across the vaginal epithelium (Brosnahan et al., 2009).
A significant clinical burden of S. aureus skin infection is also apparent in individuals with several immunodeficiency states and atopic dermatitis, a chronic disease in which up to 90% of afflicted patients harbor S. aureus in lesional and non-lesional skin (Ong and Leung, 2010). Host defense against S. aureus skin infection is multifaceted, relying most importantly on local innate immunologic control through TH17 and IL-1β driven recruitment of neutrophils in addition to the protective actions of β-defensins and the cutaneous barrier. Pathogen virulence in acute staphylococcal infection is likewise multifactorial, relying in part on α-hemolysin (Hla), a pore-forming cytotoxin secreted by almost all strains of S. aureus (Bhakdi and Tranum-Jensen, 1991). Hla is required for dermonecrotic changes in skin infection, also contributing positively to abscess size (Kennedy et al., 2010; Patel et al., 1987). Immunization strategies targeting Hla afford protection against dermonecrosis (Kennedy et al., 2010). Indeed, S. aureus is the most common bacterial pathogen that complicates atopic dermatitis lesions (Ong and Leung, 2010), demonstrated to express the V8 protease and immunomodulatory virulence factors that have also been described to adversely impact on epithelial barrier function.
There remains a need to develop effective compositions and treatments for staphylococcal and other pathogenic bacterial infections.